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Chronic myeloid leukemia: the paradigm of targeting oncogenic tyrosine kinase signaling and counteracting resistance for successful cancer therapy
- Source :
- Molecular Cancer, Vol 17, Iss 1, Pp 1-15 (2018), Molecular Cancer
- Publication Year :
- 2018
- Publisher :
- BMC, 2018.
-
Abstract
- Deregulated activity of BCR-ABL1, a nonreceptor tyrosine kinase encoded by the fusion gene resulting from the t(9;22)(q34;q11) chromosomal translocation, is thought to be the driver event responsible for initiation and maintenance of chronic myeloid leukemia (CML). BCR-ABL1 was one of the first tyrosine kinases to be implicated in a human malignancy and the first to be successfully targeted. Imatinib mesylate, the first tyrosine kinase inhibitor (TKI) to be approved for therapeutic use, was hailed as a magic bullet against cancer and remains one of the safest and most effective anticancer agents ever developed. Second- and third-generation TKIs were later introduced to prevent or counteract the problem of drug resistance, that may arise in a small proportion of patients. They are more potent molecules, but have been associated to more serious side effects and complications. Patients achieving stable optimal responses to TKI therapy are predicted to have the same life expectancy of the general population. However, TKIs do not ‘cure’ CML. Only a small proportion of cases may attempt therapy discontinuation without experiencing subsequent relapse. The great majority of patients will have to assume TKIs indefinitely – which raises serious pharmacoeconomic concerns and is now shifting the focus from efficacy to compliance and quality of life issues. Here we retrace the steps that have led from the biological acquisitions regarding BCR-ABL1 structure and function to the development of inhibitory strategies and we discuss drug resistance mechanism and how they can be addressed. Electronic supplementary material The online version of this article (10.1186/s12943-018-0780-6) contains supplementary material, which is available to authorized users.
- Subjects :
- 0301 basic medicine
Cancer Research
medicine.drug_class
Population
Resistance
Tyrosine kinase inhibitor
Protein Kinase Inhibitor
Drug resistance
Review
Biology
lcsh:RC254-282
Tyrosine-kinase inhibitor
03 medical and health sciences
0302 clinical medicine
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
hemic and lymphatic diseases
medicine
Animals
Humans
education
Protein Kinase Inhibitors
Tyrosine kinase
Tyrosine kinase inhibitors
education.field_of_study
Animal
Myeloid leukemia
Cancer
medicine.disease
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
BCR-ABL1
030104 developmental biology
Imatinib mesylate
Oncology
Drug Resistance, Neoplasm
030220 oncology & carcinogenesis
Cancer research
Imatinib Mesylate
Molecular Medicine
Magic bullet
Human
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 14764598
- Volume :
- 17
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Molecular Cancer
- Accession number :
- edsair.doi.dedup.....23a85586da3de9479777d81f01bed1dd